Heart disease remains the leading cause of death in the United States and other developed countries. Half of these deaths occur suddenly, typically from ventricular tachyarrhythmias that arise in the setting of acute ischemia, acquired heart disease or inherited syndromes including channelopathies and cardiomyopathies. Gap junction channels are responsible for normal impulse propagation and gap junction remodeling contributes to these lethal rhythm disturbances. A detailed understanding of the mechanisms responsible for gap junction remodeling are lacking, preventing the development of anti-arrhythmic strategies targeting the gap junction protein complex. Through the use of genetically engineered mice and novel high throughput genetic screens, we propose a series of experiments to more fully characterize the molecular mechanisms responsible for gap junction remodeling, with the longer term goal of identifying novel therapeutics.